Recently we have shown that carriers of a chromosome variant, the double nucleolar organizer region (dNOR), are at a 10-20 fold increased risk for conceiving a child with Down syndrome. To further establish the role of the dNOR variant in nondisjunction of chromosome 21, and possibly other chromosomes, we plan to determine and compare the rate of chromosome aneuploidy in spermatozoa from dNOR(+) and dNOR(-) males. The rate of gamete aneuploidy in the study subjects will be directly evaluated using the hamsteregg/humansperm system. Our first dNOR(-) control group will be comprised of 20 monozygotic male twin pairs. In addition to providing information about the general population rate of aneuploidy, this cohort will allow us to generate estimates of individual variation in the frequency of aneuploid sperm among genotypes. Our second dNOR(-) group will include 10 fathers in whom nondisjunction of chromosomes 21 has been shown to occur. Comparisons in the incidence of aneuploidy between the dNOR(-) cohorts will allow for tests of the hypotheses that (1) the conception of a Down syndrome offspring by dNOR(-) fathers is a random event; and (2) constitutional factors other than the dNOR variant contribute to an increased risk for the conception of an offspring with Down syndrome. The dNOR(+) study group will consist of 10 dNOR(+) fathers of trisomic patients in whom nondisjunction of chromosome 21 ws shown to have occurred, and 10 dNOR(+) male first degree relatives who have not yet conceived a child with Down syndrome. In addition to providing data to test our primary hypothesis of a difference in the sperm chromosome aneuploidy rate from dNOR(+) compared to dNOR(-)males, we will also be able to test for heterogeneity in the risk of dNOR variants on (1) different acrocentric chromosomes and (2) different genetic backgrounds. The role of the NOR in nondisjunction will also be studied by observing the distribution of meiosis I and II errors between study groups and by analyses of the relationship between sperm chromosome aneuploidy and satellite association through NOR phenotyping in lymphocytes and, if possible, spermatozoa. Therefore, the results of this study should not only allow us to more accurately estimate an individual's absolute and recurrence risk for having aneuploid offspring, but could also increase our knowledge about the mechanism(s) which actually lead to nondisjunction.